MICA: Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and reno-cardiac disease

We believe that a protein used by white blood cells to defend against microbes, called myeloperoxidase, appears to be the critical mediator in causing kidney damage in various conditions, such as vasculitis and lupus that can affect the kidneys, and is also involved in promoting accelerated furring of the arteries, that can lead to significant heart disease in patients with autoimmune diseases such as vasculitis and lupus. Interestingly, myeloperoxidase can be inhibited, apparently without ill effect. We wish to test if it is a viable drug target, by investigating whether myleoperoxidase blockers could be used to protect the kidney from damage in various disorders which lead to kidney inflammation and result in kidney failure and whether, because of its diverse roles in causing arterial damage, they may also protect from the accelerated heart disease that can be found in such patients.

Crescentic glomerulonephritis (CGN) represents a severe form of kidney injury that can occur in the context of various diseases. Common to many forms of CGN is abnormal or excessive glomerular neutrophil and monocyte activation with evidence for release of proteases and neutrophil extracellular traps (NETs). We and others have shown a significant extracellular deposition of leukocyte myeloperoxidase (MPO) in various forms of CGN and evidence for augmented circulating levels of MPO in patients with CGN. Despite its importance in innate immunity, MPO deficiency does not result in a significant clinical phenotype. We propose to investigate if MPO is a critical mediator of glomerular damage and could represent a novel therapeutic target in CGN, using preclinical models of CGN and the novel MPO inhibitor AZM198. We will test whether susceptibility to CGN is in part related to MPO deposition and whether MPO inhibitors can prevent neutrophil activation and NET formation, found in CGN. Finally, chronic autoimmune conditions leading to CGN often result in accelerated cardiovascular disease and MPO has been shown to play a critical role in atherosclerosis, so we will investigate the impact of inflammation, induced by ANCA associated CGN, on atheroma and the effect of MPO inhibition.

The impact of this research project will be both academic and clinical. On the academic side, the key discovery will be to better understand basic mechanisms mediating crescentic glomerulonephritis, with specific emphasis on systemic vasculitis, and the role played by myeloperoxidase. Data on the influence of MPO on NET formation will be of considerable interest to a wide variety of medical specialities, as mentioned previously, including nephrology, immunology, rheumatology, gastroenterology and obstetrics. Furthermore, these studies may have significant clinical impact, helping to define a novel therapeutic target, myeloperoxidase, in the various diseases that are characterised by abberant NET formation or neutrophil activation. Critically, some forms of crescentic glomerulonephritis have no current successful treatments, meaning there are still significant unmet clinical needs that this project could impact on.
In addition to the academic and clinical impact this work could have significant economic and societal impact. Crescentic glomerulonephritis is not common, but frequently leads to end-stage renal failure if not treated adequately and renal replacement therapy consumes a very significant proportion of the healthcare budget. Moreover, while individual (speciality specific) immune-mediated diseases that are characterised by neutrophil degranulation or NET formation are also uncommon, overall the burden of diseases is substantial, necessitating uptake of many health care resources. There are further economic costs incurred in managing the considerable disability resulting from prolonged immunosuppression therapy which is required for many of these neutrophil/NET dependent diseases. The ability to define novel therapies may allow for synergy with current treatments and allow lower doses of current immunosuppressants to be used, with reduced side effect profiles.